From 2011 IAS Conference: Controversies in HIV Cure Research

Summary and comments of a joined amfAR, The Foundation for AIDS Research and the International AIDS Society (IAS) satellite symposium held in Rome, July 18th 2011.

While it is known that antiretroviral therapy does not cure HIV infection, several controversies in the field of HIV cure research remain unresolved and have the potential to redirect lines of scientific inquiry including strategies aimed at curing HIV infection. This session was build around 3 main questions drawn from basic, preclinical and clinical research.

The amfAR symposium closed this first day of the IAS conference. The session was organized around 3 debates representing hot topics in HIV cure research. Each speaker was asked to take position on the topic and then a discussion was organized.

THE FIRST DEBATE WAS ABOUT THE EXISTENCE OF ONGOING VIRAL REPLICATION UNDER EFFECTIVE ART.

Mario Stevenson argued for the positive answer. cDNA intermediates are a way to study persistent replication. Raltegravir, as well as viruses lacking the integrase in vitro, lead to an increase of these dead end DNA. The Buzon paper last year in Nature Med showed an increase in episome frequency two weeks after raltegravir intensification. This can only be explained by de novo infection. The main argument against ongoing replication is the lack of resistance selection. A possible explanation is that we have a source of virions that infects other cells that are unable to replicate the virus in the way that is able to lead to resistance selection.

Franck Maldarelli argued against ongoing replication, but he mentioned that the 2 theories of ongoing replication or the release of virions by long-lived cells are not exclusive. He showed his published studies that failed to found any effect of ART intensification on low level viremia, and that viruses on long-term effective ART do not develop any genetic change in their population, not only in terms of resistance mutations but any change at all. He also raised the issue of measuring proviral DNA which contains lots of defective viruses. Maldarelli argued that we do not have definite data showing that HIV still replicates in the brain or the gut on ART. The results presented by Buzon are weird in his point of view and need to be confirmed.

Steeve Deeks animated the debate. He wanted Maldarelli to clearly say that there is never ongoing viral replication on ART. He asked him if he thinks that the subject is now closed and studies on ongoing replication are definitely useless. Maldarelli response was not black or white. Then, Deeks challenged Stevenson about the negative results of all studies but one on ART intensification. Stevenson pointed out that one of the problems is the fact that we are using non standardized assays, in particular for measuring 2 LTR. Javier Picado from the floor talked in the name of the Buzon paper and mentionned that when Raltegravir intensification was stopped, immune activation increased. David Margolis made the remark that persistence is due to cells releasing virions that can infect other cells, but not with a complete cycle of replication. Rafick Sekaly finally argued that what we are measuring in blood could not be a good picture of what is happening in tissues.

THE SECOND DEBATE WAS WHETHER CELL AND ANIMAL MODELS WILL BE INFORMATIVE IN PLANNING CLINICAL TRIALS FOR A CURE, OR IF WE WILL ONLY LEARN BY DOING THE TRIALS?

This debate was introduced by Rafick Sekaly. He said that there is not currently one animal model that recaps all the issues of HIV persistence.

Alan Landay renamed the debate as "man against monkey". He stressed that we can learn a lot on the natural course of HIV disease by studying humans and not primates with different viral strains. Furthermore, the viral set points are different in humans and primates. A lot of data have been obtained by using in vitro human cells from patients infected by HIV, and we lack primate cell lines to study HIV latency. The top human proof of concept is the Berlin patient. We already have different kinds of drugs to be tested in humans, like anti cancer agents, and we will never have the critical number of animals to prove something significant. One of these "cure" trials is the study of SAHA done by Margolis, in humans. Landay thinks that we can also learn a lot by studying HIV-infected patients with malignancies who receive these anti-cancer drugs.

Guido Silvestri argued that at a few distance from the Vatican he could not say that man and apes are the same thing... He thinks that monkey models are largely under utilized for the study of eradication. Some of these experiments are risky, and this is one major reason for testing them first in primates. A standardized non human primates resource could help saving money. But there is a need to standardize the models in terms of species, viruses, type and timing of treatment, assays, veterinarian techniques...

This topic finally induced less discussion from the floor and less passion in discussion than the previous one. Steve Deeks raised the problem of the cost between a cure trial in a human with extensive explorations and biopsies, around 20,000 USD, and the price of one monkey... Obviously everyone was preaching for their church, to get the funding in their direction...

THE THIRD DEBATE ASKED IF WE WERE MORE LIKELY TO CURE HIV BY GENE THERAPY OR BY A PHARMACOLOGIC APPROACH?

Mark Harrington introduced the topic.

Sharon Lewin defended the drug approach. She first said that gene therapy was flawed and will never cure HIV. The first problem is that there is only 1 infected cell in 1 million. The Berlin patient was not cured by bone marrow transplant, she said, but by bone marrow transplant plus total body irradiation and chemotherapy. Nucleases have to be 100% specific to be safe. This is not curently the case. There is also a safety problem with adenovirus as a delivery vector, even if it is in vitro. Drugs, on the contrary have limited, well known toxicities which are usually reversible. There are drugs, licensed in other areas, that are ready to be tested, like SAHA. The addition of immune modulators to these drugs is a promizing approach. There are new possibilities to enhance specificity, for example for HDACi. Finally, we need a cure deliverable in all places of the world, what gene therapy will not be able to offer. Lewin again argued that the risks of gene therapy are high.

Keith Jerome argued the opposite: gene therapy is the way to a cure! The Berlin patient teached us that HIV is a genetic disease. One of the main issues is the specificity of the nucleases we will use. There are good data showing that they have very good specificity and that they are safe. In the future we can design nucleases able not only to knock out the expression of some genes, like CCR5, but even proviral DNA itself. To conclude, Jerome said that the tools for gene therapy are really at hand. He, however, agreed that worldwide delivery would currently be a problem.

In conclusion, this amfAR session brought us a lot of data, induced a lot of exchanges, and was definitely one of the best sessions of this first day